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lACC Vol. 5, No.5
May 1985:35A-42A
Digitalis and the Autonomic Nervous System
AUGUST M. WATANABE, MD, FACC
Indianapolis, Indiana
Digitalis produces many of its effects in intact animals
and human beings by modifying the properties of the
autonomic nervous system. The parasympathetic limb
of the autonomic nervous system is most sensitive to these
effects of digitalis, and its properties are significantly
altered with therapeutic concentrations of the drug. These
actions are particularly important in mediating the electrophysiologic effects of digitalis. With toxic concentrations of digitalis, stimulation of sympathetic nerve ac-
Cardiac glycosides produce important effects on the physiologic properties of the nervous system. This is not surprising considering the critical role of the Na + -K + adenosine triphosphatase (ATPase) (sodium-potassium pump) in
maintaining the transmembrane sodium and potassium ion
gradients, which impart the property of excitability on
excitable tissues. The effects of digitalis on the nervous
system are clinically important because they are involved
in mediating both its therapeutic and toxic effects. The nervous system-mediated toxic effects of digitalis explain the
well known central nervous system symptoms such as psychiatric problems, neuralgias and visual changes, some of
which were first described by William Withering in his
original treatise published 200 years ago (l). In addition to
these rather generalized and mechanistically poorly understood central nervous system effects, digitalis has important
specific effects on the function of the autonomic nervous
system. The mechanisms of these latter effects are better
understood than are those of the more general central nervous system effects. The present review focuses specifically
on the interactions of digitalis with the autonomic nervous
system, effects that are involved in mediating both the therapeutic and cardiac toxic actions of the drug.
In this review, I will examine the interactions of digitalis
with the autonomic nervous system in three sections. First,
I will review the complex interactions that occur between
the sympathetic and parasympathetic nervous systems in
regulating the heart. Second, I will discuss the effects of
From the Department of Medicine and the Krannert Institute of Cardiology, Indiana University School of Medicine, Indianapolis, Indiana.
Address for reprints: August M. Watanabe, MD, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana 46223.
© 1985 by the American College of Cardiology
tivity may also occur. This latter action may be involved
in the arrhythmogenic effects of digitalis. These effects
of digitalis on the autonomic nervous system playa major
role in determining the pharmacodynamic actions of the
drug in patients. The effects of digitalis on the autonomic
nervous system also provide a setting for important interactions with other drugs that modify the properties
of the sympathetic and parasympathetic nervous systems.
(J Am Coli CardioI1985;5:35A-42A)
cardiac glycosides on the physiologic properties of the two
limbs of the autonomic nervous system. Finally, in light of
this background, I will review how the pharmacodynamic
effects of digitalis are determined by these actions on the
autonomic nervous system and summarize some of the clinical implications of these interactions.
Sympathetic and Parasympathetic Regulation
of Cardiac Function
The major system extrinsic to the heart itself that regulates cardiac function is the autonomic nervous system. This
system can be subdivided on the basis of a variety of considerations-including anatomic differences, differences in
neurotransmitters, differences in receptors which the released neurotransmitters activate and differences in physiologic effects-into two major limbs, the sympathetic and
parasympathetic nervous systems. In general, activation of
the sympathetic nervous system leads to stimulation of cardiac function, whereas activation of the parasympathetic
nervous system inhibits cardiac function. Much has been
learned during the past two decades about the complex manner in which the two limbs of the autonomic nervous system
interact in regulating the heart.
Interaction of sympathetic and parasympathetic
limbs. Autonomic regulation of cardiac function does not
result simply from reciprocal changes in sympathetic and
parasympathetic tone. Although such reciprocal changes in
tone of the two limbs of the autonomic nervous system do
occur in response to physiologic demands, there is also
interaction between the two limbs in which the parasympathetic nervous system modulates (restrains) the effects of
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DIGITALIS AND THE AUTONOMIC NERVOUS SYSTEM
the sympathetic nervous system (2,3). This interaction between the two limbs of the autonomic nervous system occurs
at two levels in the periphery, prejunctionally (that is, between the nerve terminals) and postjunctionally at the level
of the innervated cells (2,3). The parasympathetic modulation of sympathetic effects can be quite marked and can
entirely override the sympathetic effects. A clinically relevant example of such an interaction is that seen when a
mixed beta- and alpha-receptor agonist, such as epinephrine,
is administered to a subject. When this is done, the heart
rate slows down because of activation of the baroreceptor
reflex due to the hypertension which results from the alphareceptor-mediated vasoconstriction induced by the catecholamine. Even though the beta-receptors in the sinoatrial
node are being bombarded by the epinephrine molecules,
the increased vagal tone acting on the sinoatrial node can
completely dominate and override the stimulating effects of
the catecholamine, resulting in a bradycardic response. If
the subject is given atropine to block muscarinic receptors
before the administration of the catecholamine, tachycardia
as well as hypertension result. Thus, at the postjunctional
cellular level, muscarinic stimulation can completely override the effects of beta-adrenergic activation. These types
of complex interactions between the two limbs of the autonomic nervous system must be considered in order to understand the role of the autonomic nervous system in mediating the effects of digitalis on cardiovascular function.
In this section, I will summarize what is known about the
mechanisms of these interactions between the sympathetic
and parasympathetic nervous systems.
Prejunctional interaction. The terminals of sympathetic and parasympathetic fibers lie in close proximity with
one another in some regions of the heart, and in some cases
may even be enclosed by the same Schwarm cells (4). This
provides an anatomic basis for interaction between the two
limbs. In addition, various physiologic studies in isolated
hearts and in intact animal preparations (2,5-7) suggest that
endogenous acetylcholine released from vagal nerve fibers
or exogenously administered can inhibit the release of norepinephrine from sympathetic nerve terminals. From a substantial body of such evidence, it is now hypothesized that
sympathetic nerve terminals contain muscarinic receptors
that can be activated by acetylcholine released from vagal
fibers, and that this muscarinic activation inhibits the release
of norepinephrine (5).
Thus, one important mechanism for interaction between
the two limbs of the autonomic nervous system is this prejunctional muscarinic inhibition of norepinephrine release
from sympathetic terminals. Certain physiologic demands
calling for reduced sympathetic stimulation of the heart could
be met by either sympathetic withdrawal or vagal activation,
or both. If vagal tone increased more quickly than sympathetic withdrawal, the physiologic result of reduced sympathetic effect would be attained as quickly as vagal tone
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was increased, even though there might be a lag in reduction
of efferent sympathetic activity. This type of prejunctional
interaction would be effective in regulating only the release
of norepinephrine from nerve terminals. This mechanism
would have no impact in modifying the effects of catecholamines that have been released from the terminals or
that reach the beta-adrenergic receptors through the circulation, such as epinephrine derived from the adrenal medulla.
Postjunctional cellular interaction. As suggested in the
previously cited example of the hemodynamic effects of
epinephrine given to a human subject, in addition to the
prejunctional interaction between the two limbs of the autonomic nervous system, vagal influences can modulate the
cellular response to beta-adrenergic receptor activation; that
is, there is also postjunctional or cellular interaction between
the two systems. The evidence for this comes from a substantial body of isolated organ and tissue studies, some of
which were done more than two decades ago, as well as
from more recent whole animal experiments (8-11). The
studies in isolated organs or tissues, in which autonomic
innervation could not be playing a major role in modifying
cardiac function, clearly showed that activation of muscarinic receptors could powerfully modulate the positive inotropic (12), electrophysiologic (13) and metabolic (14) effects of catecholamines acting on beta-adrenergic receptors.
That is, the simultaneous stimulation of muscarinic receptors by choline esters inhibited the response of the heart to
beta-adrenergic receptor stimulation by catecholamines. In
ventricular tissues. with a few exceptions (certain electrophysiologic responses), administration of choline esters alone
produced minimal or no effect (12). However, when the
same concentration of choline esters was administered during simultaneous beta-adrenergic receptor stimulation, the
effects of muscarinic agonists became prominent, and were
manifest as a marked inhibition of the cardiac tissue response
to the catecholamine (12). Thus, this phenomenon of "accentuated antagonism, " first described by Levy and Martin
(2) in whole animal studies, also applies to isolated tissues
(3,11).
Several laboratories, including our own, have had a major interest in understanding the mechanisms for the muscarinic modulation of the cellular response to beta-adrenergic receptor activation. In our earliest studies (12), we
found that acetylcholine alone did not alter contractility of
isolated paced guinea pig ventricles, even though the choline
ester increased tissue cyclic guanosine monophosphate
(cGMP) levels to twice control values. However, when the
same concentration of acetylcholine was given simultaneously with isoproterenol, it potently antagonized the positive inotropic effect of the catecholamine (12). Acetylcholine also antagonized the positive inotropic effects of several
other agents that presumably act by increasing cyclic adenosine monophosphate (cAMP) levels, including histamine,
dibutyryl cAMP and the phosphodiesterase inhibitors the-
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ophylline and papaverine (12). These results suggest that
the antagonistic effects of acetylcholine were directed at
cAMP actions within the cell and not specifically at the
beta-adrenergic receptor, and this conclusion has been supported by numerous subsequent studies from our laboratory
and others (II). Subsequent studies showed that acetylcholine could antagonize certain electrophysiologic effects of
catecholamines, such as stimulation of the "slow response"
(13) and catecholamine activation of glycogen phosphorylase (14).
The subcellular mechanisms by which acetylcholine
produces its antagonism of beta-adrenergic effects are still
being elucidated, but substantial insight has already been
gained. In isolated heart preparations (15,16), it has been
shown that the simultaneous administration of acetylcholine
can significantly attenuate the amount of cAMP generated
in response to beta-adrenergic receptor stimulation. It appears likely that inhibition of adenylate cyclase is involved
in this muscarinic effect. It is now generally accepted that
adenylate cyclase is a dually regulated enzyme, and that
certain receptors coupled to it can stimulate activity, whereas
other receptors can inhibit enzyme activity (17,18). Thus,
in certain conditions and with certain species, muscarinic
inhibitory regulation of adenylate cyclase activity likely
modulates the response of the heart to beta-adrenergic receptor stimulation by regulating the amount of cAMP generated (16,18).
It appears likely that muscarinic agents act by an additional mechanism to inhibit the response of the heart to betaadrenergic receptor stimulation. In many different experiments from several laboratories (12,19-21), it has been
shown that, under certain conditions, muscarinic agonists
can potently antagonize cardiac responses to beta-adrenergic
receptor stimulation without producing a proportionate, or
in some cases any, reduction in cAMP levels. It has also
been shown that choline esters can antagonize the cardiac
stimulatory effects of agents that elevate cAMP levels without stimulating adenyl ate cyclase. For example, acetylcholine can antagonize the positive inotropic effects of phosphodiesterase inhibitors (12,21). Choline esters can also
potently antagonize the positive inotropic effects of the diterpene forskolin, which is thought to act directly on the
catalytic subunit of adenylate cyclase, independently of
components of the enzyme that are regulated by muscarinic
receptors (22).
These types of evidence have provoked examination of
"distal" steps in the cascade of reactions that occur when
cellular cAMP levels are increased. An area of focus in our
laboratory has been phosphorylation of certain membraneassociated proteins thought to be involved in mediating the
intracellular effects of cAMp. We have found (23) that
muscarinic agonists can markedly attenuate the phosphorylation of certain proteins in intact cardiac muscle without
reducing the tissue levels of cAMP. Thus, in addition to
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inhibitory regulation of adenylate cyclase, muscarinic agonists can also inhibit phosphorylation of proteins induced
by agents, such as catecholamines, which elevate cAMP
levels. In the intact heart in situ, it is likely that both of
these mechanisms-that is, inhibition of adenylate cyclase
and attenuation of protein phosphorylation-operate to mediate the postjunctional cellular muscarinic inhibition of cardiac responses to beta-adrenergic receptor stimulation.
To summarize, when physiologic demands require withdrawal of sympathetic influences on the heart, in addition
to reciprocal changes in sympathetic and parasympathetic
tone, vagal activation modulates the effects of the sympathetic nervous system. This modulatory interaction between
the sympathetic and parasympathetic systems occurs at two
levels, prejunctionally between nerve terminals and postjunctionally at the cellular level. The cardiovascular effects
of digitalis, which importantly modify especially parasympathetic tone, must be considered in light of these concepts.
Effects of Digitalis on Autonomic Nervous
System Function
Many experiments have been done over the years to
characterize the nature of the effects of digitalis on the
autonomic nervous system and to attempt to explain the
mechanisms for these effects. These studies have been summarized in recent comprehensive reviews (24,25). Although
there is not total agreement on the nature and clinical significance of the effects of digitalis on the autonomic nervous
system, the following points seem well established and generally accepted: I) the actions of digitalis on the autonoinic
nervous system are very important clinically and play a
major role iri determining the clinical pharmacodynamic
effects of the drug; 2) with therapeutic concentrations of the
drug, the predominant effect is activation of vagal tone; and
3) with toxic concentrations of the drug there may be activation of sympathetic tone. In this section, I will discuss
some of the mechanisms by which digitalis is thought to
produce these changes in autonomic nervous system tone.
With therapeutic concentrations of digitalis in intact animals or human beings, the primary cardiac effect of the
changes in the autonomic nervous system is one of restraint
or inhibition of cardiac function. That is, vagal activity is
increased while sympathetic activity is either unchanged or
reduced. These autonomic changes have major electrophysiologic effects, particularly on supraventricular structures, that are very important for the antiarrhythmic properties of digitalis.
Effects on the Parasympathetic Nervous System
On the basis of both animal and clinical studies, it has
long been known that an important mechanism by which
digitalis alters cardiac function is its effects on the para-
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sympathetic nervous system . The cardiac effects of digitalis
are often referred to as "direct" and "indirect." The former
refers to the effects of digitalis that are due to its action on
cardiac tissues themselves, whereas the latter refers primarily to the effects that are mediated by increased activity
of the parasympathetic nervous system . With therapeutic
levels of the drug, the indirect effects may actually be more
important than the direct effects, because the indirect effects
of digitalis occur with a lower level of the drug than that
required to produce the direct tissue effects. Digitalis produces
this effect of increased vagal activity by acting on several
of the components of the parasympathetic nervous system,
both in the central nervous system and in the periphery.
Various neurophysiologic studies (24) have shown that digitalis can modify afferent autonomic input into the brain,
central nervous system processing of these input signals and
efferent vagal nerve activity.
Effect on baroreceptors. A major mechanism for the
augmented vagal tone seen with therapeutic concentrations
of digitalis appears to be its effects on afferent systems .
Digitalis can activate reflexogenic areas of the cardiovascular system, such as arterial baroreceptors and chemoreceptors, and other afferent nerve fibers in the nodose ganglion and the heart (24). A variety of experiments have
examined the effects of digitalis on baroreceptors . Cardiac
glycosides have been perfused selectively into carotid baroreceptors or topically applied to the area and the physiologic effects monitored either by observing hemodynamic
responses (for example, heart rate and blood pressure) or
by directly recording carotid sinus nerve activity (26-29) .
Similar experiments (30) have been done with isolated aortic
arch preparations coupled with direct measurements of the
electrical activity of aortic depressor nerves. The accumulated evidence from these various studies indicates that digitalis causes excitation of baroreceptors in the carotid sinus
and aortic arch (24).
Effect on cardiac receptors. Direct application of digitalis to the epicardium of the left ventricle of dog hearts or
selective injection into the anterior descending branch of
the left coronary artery leads to hypotension and bradycardia
(31,32) . These results were interpreted as indicating that
digitalis sensitized cardiac receptors located within the left
ventricular myocardium.
Thus, digitalis sensitizes baroreceptors and cardiac receptors so that afferent input from the cardiovascular system
to the brain is augmented. This results in recruitment of
inhibitory influences from the autonomic nervous system,
including increased vagal activity and perhaps withdrawal
of sympathetic activity .
Effect on efferent pathways. Digitalis also acts dn efferent pathways in the parasympathetic nervous system to
augment vagal tone. Effects have been demonstrated on
autonomic ganglia as well as on the electrical activity of
efferent parasympathetic nerves . The treatment of isolated
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ganglia preparations with digitalis glycosides sensitized the
preparations to the activating effects of acetylcholine, -the
normal neurotransmitter for the ganglia (33,34). Digitalis
selectively administered to ganglia also enhanced the physiologic response to preganglionic nerve stimulation (34).
Electrophysiologic studies (35) have documented the direct
effects of digitalis on autonomic ganglia. Accordingly, an
important mechanism by which digitalis augments vagal
tone is by improving ganglionic transmission.
Potentiation of end organ responses to acetylcholine. Digitalis also augments the end organ responses to
vagal stimulation or administered acetylcholine. These effects are most readily demonstrated in the sinoatrial or atrioventricular nodes. They have been examined with electrical
stimulation of postganglionic parasympathetic nerves or
adtninistration of acetylcholine, before and after administration of digitalis to the preparation (27,36-38).
Thus, therapeutic concentrations of digitalis produce effects on several components of the autonomic nervous system, all of these effects leading to an augmentation of vagal
tone. The most important of these effects are sensitization
of afferent systems, improvement in ganglionic transmission
in efferent vagal nerves and potentiation of end organ responses to acetylcholine.
Parasympathetic modulation of sympathetic effects.
A direct effect of therapeutic concentrations of digitalis on
the sympathetic nervous system is less well established than
that for the parasympathetic nervous system. However, even
if there is no direct effect of cardiac glycosides on the
sympathetic nervous system when the drug is present in
therapeutic concentrations, there are important indirect effects resulting from the parasympathetic modulation of sympathetic effects. With increased vagal tone, norepinephrine
release from sympathetic terminals should be inhibited by
the prejunctional interaction between the two systems. In
addition, the augmented release of acetylcholine and the
potentiation of end organ responses to acetylcholine should
magnify the postjunctional cellular inhibition of the cardiac
response to beta-adrenergic receptor stimulation. Thus, because of the interactions discussed in the first section of this
review, therapeutic levels of digitalis should significantly
modify the cardiac response to sympathetic as well as parasympathetic stimulation.
Effects on the Sympathetic Nervous System
Similar to the situation with the parasympathetic nervous
system, digitalis alters the properties of the sympathetic
nervous system by acting at several levels in the system .
The site of action and the nature of the effect are dependent
on the concentration of digitalis to which the sympathetic
tissues are exposed. However, review of a large body of
published data (24) suggests that sympathetic effects occur
only with substantially higher concentrations of digitalis
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than those required to produce parasympathetic effects, Accordingly, while parasympathetic effects are important in
mediating therapeutic effects of digitalis, sympathetic effects probably come into play, if at all, only with toxic
concentrations of the drug,
Augmentation of efferent sympathetic nerve activity. A variety of experiments have been performed to assess
the possible effects of digitalis on the central nervous system
(24), Most of these have shown that with relatively high
concentrations of digitalis in the brain, there can be increases
in efferent sympathetic nerve traffic, The experimental approaches have included direct administration of digitalis into
the central nervous system, coupled with monitoring of efferent nerve activity and physiologic responses (39-41),
Although the results of these studies have not all been in
agreement, a general consensus is that with large "arrhythmogenic" doses of digitalis, there can be central augmentation of efferent sympathetic nerve activity, An additional
interesting conclusion from some of these studies is that the
increased efferent nerve traffic can be nonuniform (42), If
this were to occur in intact animals or human subjects, it
could be significant for the development of reentrant cardiac
arrhythmias because the nonuniform sympathetic influences
on the ventricles would lead to dispersion of refractoriness,
Additional evidence to support the role of increased efferent
sympathetic activity in the arrhythmogenic effects of digitalis is the observation in animal models that ablation of
efferent sympathetic nerves or blockade of beta-adrenergic
receptors increases the dose of digitalis required to produce
toxic arrhythmias (39,40,43,44),
Effect on sympathetic nerve terminals. Numerous
studies have also examined the effect of digitalis on the
handling of catecholamines by sympathetic nerve terminals,
Again, the conclusion regarding these effects is not uniform,
However, many studies (24,45,46) suggest that digitalis, at
least in large concentrations, can induce release of catecholamines and prevent catecholamine reuptake. Both of
these effects would result in cardiac stimulation and, coupled with the central nervous system-mediated increase in
efferent nerve traffic, would produce an overall effect of
increased sympathetic tone, This mechanism might also be
involved in the arrhythmogenic effects of digitalis,
Despite this evidence from animal studies, it is not generally accepted that increased sympathetic nervous system
activity plays an important role in the arrhythmias associated
with digitalis toxicity observed clinically, It is also important
to point out in this context that antiadrenergic drugs are not
generally known to be efficacious in treating arrhythmias in
patients suffering from digitalis toxicity,
To summarize, the interactions of digitalis with the autonomic nervous system are well documented, and these interactions are important in determining the clinical effects
of the drug, With therapeutic levels of digitalis, the parasympathetic effects are most prominent. With higher, toxic
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concentrations of the drug, sympathetic effects may become
manifest and might contribute to the arrhythmogenic effects
of digitalis,
Clinical Significance of Digitalis Interactions
With the Autonomic Nervous System
Inotropic effects. As mentioned previously, the interactions of digitalis with the parasympathetic nervous system
occur with therapeutic concentrations of the drug, indeed
with a lower concentration than that required to produce
direct cardiac effects, These parasympathetic effects are, if
anything, negatively inotropic, The augmented parasympathetic tone would tend to decrease contractility of the atria
directly, and would also tend to antagonize the positive
inotropic effects of the sympathetic nervous system on the
ventricles, Furthermore, the bradycardic effect of increased
vagal activity would reduce cardiac output. Thus, with therapeutic concentrations of digitalis, the consequence to the
heart of the effects on the autonomic nervous system is
exactly opposite that which results from the direct myocardial effects (inhibition of the sodium-potassium pump),
This is why the positive inotropic effects of digitalis in intact
animals and in human beings are quite small and often
difficult to demonstrate, This is also perhaps a reason why
it has been difficult to document sustained positive inotropic
effects of digitalis in patients with normal sinus rhythm, It
must be kept in mind, however, that the "baseline" autonomic tone in patients with congestive heart failure is different from that in subjects without heart failure, In patients
with heart failure, vagal tone is reduced while sympathetic
tone is high, It is possible that the responsiveness of the
autonomic nervous system in patients with heart failure is
altered, so that the foregoing parasympathetic effects are
not so prominent. If this were the case, the direct myocardial
actions might predominate and in this setting the positive
inotropic effects might be more prominent.
Electrophysiologic effects. The actions of digitalis on
the parasympathetic nervous system are important for the
clinical electrophysiologic effects of the drug, These electrophysiologic effects are particularly marked on supraventricular structures including the sinoatrial node, the atrial
myocardium and the atrioventricular node, In subjects who
have normal sinus rhythm, administration of digitalis may
slow the heart rate, In patients who have paroxysmal supraventricular tachycardia, the effect of digitalis, acting by way
of the parasympathetic nervous system on the atrioventricular node, might result in reduced conduction to the ventricles and thereby a slower ventricular response. Alternatively, because of the potentiation of vagal effects, digitalis
might make cardioversion possible in a patient with a paroxysmal supraventricular tachycardia using maneuvers to
augment vagal tone, such as carotid sinus massage. In pa-
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DIGITALIS AND THE AUTONOMIC NERVOUS SYSTEM
tients with atrial fibrillation, the vagotonic effects of digitalis
on the atrioventricular node slow the ventricular response.
Because all of these clinical electrophysiologic effects of
digitalis are mediated indirectly by the action of the drug
on the vagus, the effects are dynamic and can change rapidly
in response to altered physiologic states of the patient. For
example, in patients with atrial fibrillation, the ventricular
response may be slow while the subject is at rest and vagal
tone is high. However, with exercise or emotional excitement, when vagal tone is reduced and sympathetic tone
increased, the ventricular rate may increase markedly. The
ventricular response in such a patient becomes independent
of the state of autonomic tone only when the patient is "well
digitalized," that is, when circulating levels of the drug are
high enough to produce direct effects on the atrioventricular
node.
Effect on cardiac arrhythmias. Under certain conditions, therapeutic levels of digitalis might also have antiarrhythmic effects on ventricular arrhythmias. Contrary to
long-held dogma, there is now general agreement from substantial data that vagal fibers innervate the ventricles as well
as supraventricular structures (2,3). The vagal innervation
of the ventricles is less dense than that of supraventricular
structures and also less dense than sympathetic innervation.
Vagal innervation of the ventricles is also not as diffuse as
sympathetic innervation. The vagal innervation is richest in
the ventricular septum, particularly in the region of the
bundle branches (47). Evidence for vagal innervation of the
ventricles derives from histochemical staining of some of
the enzymes contained in vagal fibers, direct measurement
of acetylcholine content in the ventricular myocardium and
physiologic studies (47--49). In physiologic experiments with
intact conscious dogs (50), it has been shown that vagal
tone restrains the ventricular response to beta-adrenergic
receptor stimulation. Other experiments in dogs (6,7) have
also demonstrated that vagal stimulation attenuates the overflow of catecholamines from the heart that results from
sympathetic stimulation. Thus, there seems ample evidence
for physiologic antiadrenergic effects of the parasympathetic
nervous system in the ventricles. If a patient has a ventricular
arrhythmia that is dependent on sympathetic stimulation,
then digitalis augmentation of vagal tone might be antiarrhythmic in that setting.
One of the most important manifestations of digitalis
toxicity is cardiac arrhythmia. Virtually all types of cardiac
arrhythmias have been reported to occur with digitalis. However, the classic abnormalities are a combination of block
with evidence of enhanced automaticity (for example, paroxysmal atrial tachycardia with atrioventricular block). To
what degree these arrhythmias are dependent on digitalis
effects on the autonomic nervous system is not clear. As
discussed earlier, high concentrations of digitalis can augment sympathetic tone both by effects in the central nervous
system to increase efferent nerve activity and by enhance-
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ment of catecholamine release or blockade of catecholamine
reuptake. Animal studies (24) indicate that larger doses of
digitalis are required to produce lethal arrhythmias when
the sympathetic nervous system is ablated or beta-adrenergic
receptors are blocked. It is possible that such sympathetic
mechanisms are operative in some patients who have cardiac
arrhythmias secondary to digitalis toxicity. However, antiadrenergic drugs are not generally considered as first-line
therapy in arrhythmias due to digitalis intoxication.
Drug Interactions
Class I antiarrhythmic agents. Because so many of the
pharmacodynamic effects of cardiac glycosides are mediated
through the autonomic nervous system, important interactions can occur between digitalis and other drugs that act
on the parasympathetic or sympathetic nervous systems.
Any drug that possesses anticholinergic activity will antagonize the vagotonic effects of digitalis. A clinical situation
in which this type of interaction must be anticipated is when
digitalis is combined with certain class I antiarrhythmic
drugs in patients with atrial fibrillation. Drugs such as disopyramide and quinidine have quite potent anticholinergic
activity (51) in addition to their antiarrhythmic properties.
In radioligand binding assays it has been shown that this
anticholinergic activity is due to direct interaction of these
drugs with muscarinic cholinergic receptors (51). If, in a
patient who has atrial fibrillation, the ventricular response
is satisfactorily controlled entirely because of the vagotonic
action of digitalis, the addition of a drug such as disopyramide or quinidine will result in marked increases in the
ventricular rate, sometimes with disastrous clinical consequences. This is why it is important to be certain that such
patients have a sufficientamount of digitalis present to produce
direct as well as indirect effects before an antiarrhythmic
agent is added.
Antiadrenergic agents. Clinically important drug interactions can also occur between digitalis and antiadrenergic agents. Because of the parasympathetic modulation
of sympathetic effects discussed in the first section of this
review, even with therapeutic concentrations digitalis can
produce antiadrenergic effects. If digitalis is given to a patient who is also receiving antiadrenergic drugs, the vagotonic effects of the glycoside might be very prominent, even
to the point of producing adverse clinical effects. Accordingly, patients with normal sinus rhythm may experience
excessive sinus bradycardia or occasionally even heart block.
Patients with atrial fibrillation may have excessively slow
ventricular responses that may produce, at the least, fatigue
and, at the worst, syncope or sudden death. Theoretically,
any of the antiadrenergic drugs could produce such adverse
interactions with digitalis. The antihypertensive agents reserpine, alpha-methyldopa, clonidine and guanabenz all could
potentiate the vagotonic actions of digitalis. Beta-adrenergic
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receptor blocking drugs are perhaps the most important agents
to be remembered in this context because of their potency
as antiadrenergic agents and their wide usage in patients
who may also need digitalis.
Calcium antagonists. Certain of the calcium antagonists might also be expected to interact with digitalis to
produce potentially undesirable electrophysiologic effects .
Verapamil and diltiazem both impede conduction through
the atrioventricular node and are, therefore, useful in treating patients with atrial fibrillation (52). If these agents are
combined with digitalis, the effect of the combination could
be more marked than desirable. Sometimes digitalis and one
of these calcium antagonists are combined intentionally to
control the ventricular response to atrial fibrillation. The use
of this drug combination should be done with care and with
knowledge of the potential adverse interaction.
Conclusions
In intact animals and patients, the pharmacodynamic effects of digitalis are mediated to a great degree by the effects
of the drug on the autonomic nervous system. These autonomic effects are particularly important for the clinical electrophysiologic effects of the drug. The vagotonic effects of
digitalis explain many of its electrophysiologic eftects on
supraventricular structures. Digitalis stimulation of sympathetic tone might participate in the arrhythmogenic effects
of the drug, although the clinical importance of sympathetic
stimulation is not as well established as IS the importance
of the vagotonic effects. The positive inotropic effects of
digitalis are not mediated by the effects of the drug on the
autonomic nervous system. If anything, the vagotonic effects of digitalis would tend to produce negative inotropic
effects. It is important to remember the effects of digitalis
on the autonomic nervous system in order to understand its
pharmacodynamic effects and to be able to predict and understand interactions of digitalis with other drugs that act
on the autonomic nervous system.
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